Cystic fibrosis (CF) is a common lethal genetic disease caused by mutations in the CFTR gene. Gene transfer to airway epithelial could represent an important advance in the treatment of CF lung disease, the main cause of morbidity and mortality. The three Projects in this Program interact closely to focus on issues critical to developing gene transfer for CF. Project 1 has made significant progress on a common problem with gene transfer vectors: limited efficiency for differentiated airway epithelial. The investigators have combined the advantages of viral and non-viral vectors to markedly enhance efficiency. The investigators how investigate the underlying mechanisms, adapt the system to other vectors, and proceed to study the interaction with the epithelial and the host. Project 2 also focuses on the limited efficiency of gene transfer vectors. The investigators have made important progress in understanding the biology of adenovirus vectors and their receptors on airway epithelia and have developed novel vectors with greatly improved efficiency. Building on preliminary data, they also adapt a powerful combinatorial approach to identify novel ligands that will be of value for gene transfer with many different vectors. Project 3 has very encouraging data on use of integrating vectors for gene transfer. The investigators have discovered novel ways to allow these vectors to transfer gene to differentiated airway epithelial. They now focus on issues central to the use of any integrating vector, including identification of cells that can be targeted to generate persistent transgene correction of the CF defect. The Projects are supported by a Cell Culture Core, a Gene Transfer Vector Core, and an Administration Core. Importantly, results from all three from all three projects will have implications for many different approaches to gene transfer. The combined effort of the enthusiastic group of investigators will yield new knowledge. The combined effort of the enthusiastic group of investigators will yield new knowledge to further the long-term goal of developing gene transfer to CF.